Ranolazine is approved for chronic stable angina. Its anti-anginal mechanism is distinct from nitrates, beta-blockers, and calcium channel blockers. It acts by inhibiting:

• A Fatty acid beta-oxidation in cardiomyocytes, shifting metabolism to glucose oxidation
• B IKr (hERG) potassium channels to prolong action potential duration
• C Late sodium current (INa,L) in ischaemic myocardial cells, reducing calcium overload ✓
• D Ryanodine receptor-2 (RyR2) calcium release channels in the sarcoplasmic reticulum

Explanation

Ranolazine inhibits the late (sustained) sodium current (INa,L) that becomes abnormally enhanced during myocardial ischaemia. This late inward Na+ current increases intracellular Na+, which impairs Na+/Ca2+ exchanger function, leading to calcium overload, diastolic dysfunction, and increased wall tension (increasing oxygen demand). By blocking INa,L, ranolazine reduces calcium overload and diastolic wall tension without significantly affecting heart rate or blood pressure. It also prolongs the QTc interval (a side effect), which is unrelated to its therapeutic mechanism. Partial fatty acid oxidation inhibition was the originally proposed mechanism but INa,L inhibition is now considered the primary mechanism.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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Written and medically reviewed by the StethoPrep medical team.